TW200942242A - New drospirenone/17β-estradiol regimen, pharmaceutical combination product and kit for performing this regimen - Google Patents

Abstract

The present invention relates to a triphasic pharmaceutical combination product comprising 24 consecutive daily dosage units in its three phases comprising in each phase of the triphasic product 6 to 10 daily dosage units wherein the amount of drospirenone in each daily dosage in each phase is the same and is from 1.5 to 3.0 mg and the amount of 17 β -estradiol increases from 1.0 mg in each dosage unit in the first phase to an amount of 2.0 mg of 17 β -estradiol in the third phase and wherein the amount of 17 β -estradiol in each daily dosage unit of the second phase is more than 1.0 mg and less than 2.0 mg and 4 active ingredient-free placebo pills or other indications to show that the daily administration of the 24 dosage units is to be followed by 4 pill-free or placebo pill days.

Description

200942242 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition containing drospirenone (DRSp) and 17β-estradiol (E2) for human contraception and peri-menopause A novel treatment for women's contraception and hormone therapy. [Prior Art] The 〇 C (oral contraceptive) containing drospirenone which is available is the product Yasmin, Yasminelle and Yaz. For hormone therapy, Angeliq, a product containing drospirenone and 17-estradiol, has been developed. Standard contraceptive pills are administered over a 28-day cycle, usually with 21 days of active pills containing progesterone plus estrogen, followed by 7 days of hormone-free or inactive pills (21+7 courses). Recently, the administration of active pills has been extended to 24 days, with no hormones for only 4 days (24+4 courses). In addition, extended treatments have been developed in which active pills are administered continuously for up to 3 months (84+7 courses). This extended treatment is a choice for women who wish to reduce the frequency of withdrawal bleeding for convenience or because of symptoms and illness associated with menstruation and hormone withdrawal.

Synthetic progesterone drospirenone has pharmacodynamic properties very similar to progesterone and differs from classical progestin in that it is derived from snail vinegar. In addition to its progestational activity, drospirenone is mainly responsible for its anti-locking activity. Based on these properties of snails, salt and water retention and blood pressure lowering effects were observed in individuals with hypertension. The affinity of the snail network to the mineralocorticoid receptor is about 5 times that of the sclerotin (naturally occurring mineralocorticoid). The combination of drospirenone and acetylene (EE) has been developed for contraception in fertile women (daily administration of 3 mg DRSP 139091.doc 200942242 in combination with 2〇 Mg or 30 EE, 21 days and 24 days of treatment). In addition, several successive combinations of snail steel and 17·β-estradiol have been developed for hormone therapy in postmenopausal women. The peri-menopausal period marks the period in which the female body begins to change to the menopause. Peri-menopause includes years leading to menopause (about 2 to 8 years) plus the first year after the final menstrual period. During this period, ovarian function declines and body estrogen levels decline. For most women, this time is between 35 and 5 years old.

between. Most perimenopausal women experience changes in their menstrual cycle. When the estrogen content begins to decline, the period of the menstrual cycle may be shortened, and thus the (10) cycle can be shortened from 28-3 days to 24-26 days, resulting in more frequent ^ other women begin to have Long cycle because it does not ovulate frequently. These changes can vary greatly from individual to individual. In addition, this estrogen content loss/fluctuation can cause many disorders: hot flashes, increased vaginal dryness, sleep problems, mood swings, pMs-like symptoms, decreased libido impulses, breast tenderness, and many other signs and symptoms. SUMMARY OF THE INVENTION The present invention is directed to providing a novel decontamination pill treatment and a pharmaceutical combination product useful as oc. This product combines natural estrogen E2 with synthetic progestin DRSP. #Pharmacological characteristics are closely related to natural progesterone progesterone, but in contrast to progesterone, it is effective to achieve bioavailability via oral route. It is also an object of the present invention to provide a course of treatment that allows for the simultaneous use of drospirenone-related benefits throughout the woman's complete menstrual cycle. Another object of the present invention is to provide a treatment with a lower load per fetus and total cycle estradiol 139091.doc 200942242. EP 0 253 607 discloses the use of a composition comprising the following estrogens selected from the group consisting of estrogens 0.075-1.50 mg 17β-estradiol, 0.012-0.025 mg ethinyl estradiol and 0.025-0.050 mg aldol ether And a progestogen selected from the following: 0.035-0.085 mg levonorgestrel, 0.015-0.060 mg diprene _, 0.035-0.085 mg desogestrel, 0.035-0.085 mg 3-keto deoxypregnene and hydrazine · 10-0.30 mg of crocodone, which is used to make a hormone replacement therapy and contraceptive dosage form for premenopausal women by the following method: from the third day of the menstrual cycle, the dosage form will be administered to the temple for 3 to 26 days. The pills were not administered or the blank pills were administered for 2 to 5 days, and the administration cycle was 28 days in total. This composition is not intended to be used as a contraceptive for younger women. There is also no mention of drospirenone as a possible progestogen component. A step-by-step estrogen contraceptive that reduces or eliminates estrogen during the initial stages of a multi-stage estrogen/progestin contraceptive treatment, and does not resemble contraceptive work or periodic control, is the subject of EP! 689 411 B1. The daily dose of estrogen (ie ethinyl estradiol) in the first stage of the preferred composition is zero or very low, ie 5 Μ ethinyl estradiol, and in the second and third stages The daily dosage of ethinyl estradiol is quite high, ie, 13909 丨.doc 200942242 is 30 pg and 35 pg ethinyl estradiol, respectively. The total amount of ethinyl estradiol in each cycle (24 days of administration) is 520 pg, and the current single-stage oral contraceptive, Yuezi (YAZ), has a total of 480 pg of estradiol per administration cycle (also Each active administration period is administered with 24 days of active ingredient). According to an exemplary preferred composition, the amount of gonadotropin (i.e., acetylene acetate) is the same per day.

A single-stage 24+4 course of oral contraceptives that can be used as a younger female is described, for example, in PCT/EP94/04274 and US RE37,564 E. Technical Solution 1 of this patent relates to a combination product for oral contraception comprising: (a) 23 or 24 dosage units each containing from more than 2 mg to 6.0 mg 17β-estradiol and hydrazine 〇 2 mg of ethinyl estradiol estrogen, and a progestin selected from 1.5 mg to 3.0 mg drospirenone and 1 mg to 2 mg of acetic acid ring name, and () knife 5 or 4 inactive ingredients to comfort Pills or other indications that do not be administered with a pill or a placebo pill after a daily dose of 2 or 24 doses of the respective unit, respectively, for $ or 4 days. The object of the present invention is achieved by a three-stage pharmaceutical combination product comprising 24 consecutive daily dosage units in eight stages, wherein the three-stage color production comprises 6 to 10 sword weight units, each of which In the stage, the name '== snail _ is the same amount and is j 5 to 3 〇mg, and - :: is 1.0 mg 17β in each dosage unit in the first stage, one yeast is increased to the third The amount of 2〇mgi7p_ in the stage of each dose is 139091.doc 200942242 The amount of alcohol' and wherein 1 of the 17β_estradiol in each of the second-day daily dosage units is greater than l.〇mg and less than 20 mg And 4 inactive ingredient placebo pills' or other indications that do not administer the pill or place a placebo pill 4 days after the administration of each of the 24 dosage units. In one embodiment of the invention, the dosage unit in each stage contains 3 mg of drospirenone. In another embodiment the dosage unit in the second stage contains 丨5 mg 17β-estradiol. According to a preferred embodiment of the invention, each of the three stages has 8 剂量 dosage units. The invention also relates to a kit comprising the above combined product. In accordance with the present invention, this novel course of administration has been found to ensure reliable induction of withdrawal bleeding prior to re-start of each dose of DRSP/E2 administration. The novel treatment provides an acceptable summary of bleeding parameters such as total days of delivery, bleeding intensity, length of withdrawal bleeding, and the like. The advantages of the treatment of the present invention can be summarized as follows: A gradual increase in the dose of Ε2 stabilizes the endometrium, thereby achieving good cycle control (intra-cycle bleeding and low incidence of spotting). ~ At the end of the treatment cycle, a dose of 2. 〇mg of Ε2 causes rapid hormonal withdrawal, which in turn leads to safe and reliable immediate withdrawal. This is important because only 4 days of further treatment will continue. At the end of the treatment cycle, the predominance of estrogen ensures a reliable intrauterine: proliferative both estrogen receptor and progestin receptor, and thus makes the lining of the lininger sensitive to progesterone. 139091.doc 200942242 The dose of E2 administered is sufficient for the course of treatment to include 'normal physiological bone mineral density. In the case of the ingestion of the wrong pill, the effect of maintaining contraception is maintained at the expense of the sustained high dose. Substituting E2 for E2, although the second is expected to provide significant benefits. One of the beans & hangs, such as liver protein biosynthesis, has less effect on the metabolic parameters of the battle. In the present invention, another carefully - - ^ . , in addition to estrogen in each daily dosage unit

曰 = = hydrogen folate, and in the absence of any hormones: 3 in the early position with four gas folate. Contains estrogen and/or progesterone and 5·methyl-(6S)-tetrahydrofolate

The medical composition is described in WO 〇 6/1.35, which is incorporated herein by reference. W〇 2〇〇6/12〇035 reveals that although it can prevent diseases caused by folic acid deficiency, i_ does not obscure the symptoms of vitamin B" lack of oral contraceptives. The respective administration courses ensure that the consumer of the (4) composition of the present invention is also reliably <RTI ID=0.0>> These treatments are also applicable to the homozygous or heterozygous polymorphism of the indolyltetrahydrofolate reductase in the user, which adversely affects the availability of folic acid for the body and thus disadvantageously Affects its biological activity in preventing neural tube defects. The addition of 5-methyl-(6S)-tetrahydrofolate to the pharmaceutical combination of the present invention serves the same purpose as in WO 2006/120035. Reference to 5-methyl-(6S)-tetrahydrofolate in the form of the present invention means 5-methyl-(6S)-tetrahydrofolate (N-[4-[[(2-amine) Base_1,4,5,6,7,8-hexahydro-4-oxo-5-methyl-(6S)-acridinyl)methyl]amino]benzylidene]_L-glutamine The free acid form of the acid) and the pharmaceutically acceptable salts and modifications. 13909l.doc 200942242 The pharmaceutically acceptable salt is intended to be pharmacologically and pharmaceutically acceptable. The pharmacologically and pharmaceutically acceptable salts can be metal or alkaline earth metal salts. Preferably, it is a sodium salt, a potassium salt, a magnesium salt or a calcium salt. Calcium salts are especially preferred. For example, 5-f-group-(10), the calcium salt of hydrogen folate (metaphin (p-valent)) (especially preferred according to the invention) is used between the call and the 1 bark, preferably in the form of Up to 1 mg, particularly preferably (5) is equivalent to a so-called folic acid or 416 Mg 51 group - called tetra &#acid (metafoiin).

The crystalline modification disclosed in EP 1044975 is a more suitable 5^-based (6S)-tetrahydrofolate repair type. The invention also refers to a pharmaceutical combination product for performing the above treatments.

The placebo key shot is introduced on the day of the intake of the money, with the aim of increasing female compliance and not forgetting to take the pills daily. According to an embodiment of the present invention, in the case where the pharmaceutical composition also contains 5_f & tetrahydrofolate, the 'hormone-free placebo' also contains the 5-methyl-(6S)·tetrahydrogen. The folate is preferably present in an amount equivalent to the daily dose. Phases In the new process and pharmaceutical combination products that combine a single-stage DRSP treatment with an increasing E2 dose, a high level of nest inhibition is achieved. The increase in E 2 dose also offsets all possible benefits of estrogen receptor modulation during the treatment cycle to effectively maintain drospirenone during the full administration period. In the case of +, these benefits are therapeutic activity in the treatment of PMDD (pre-menu: brother 'J, powder 139091.doc -10- 200942242 thorns> and drospirenone due to its counteracting estrogen The ability of water to retain the action of anti-mineralocorticoids to keep the body weight almost unchanged. Other snails _ benefits include lowering the blood pressure of women with pre-hypertension and hypertension. [Embodiment] In the clinical study, the course of treatment is about ovulation inhibition and The effect of withdrawal of withdrawal bleeding is evaluated by this study to assess the ovulation inhibition of the novel course of treatment. The bleeding pattern, cycle control and tolerability of the course of treatment are also assessed. Health between the ages of 18 and 35 A multicenter, double-blind, randomized, parallel-group study was conducted in 7 volunteer cycles to evaluate the cycle control and safety of oral contraceptives containing 17β-estradiol (E2) and drospirenone (DRSP). About 100 volunteers were treated according to the following courses of treatment. The route of administration was oral.

Day 1-8 · 1 mg Ε2+3 mg DRSP Days 9-16: 1.5 mg E2+3 mg DRSP Days 17-24: 2 mg E2+3 mg DRSP Day 25: Placebo Day 26: Consolation Day 27: Placebo Day 28: Placebo These volunteers (healthy female volunteers, ages 8 to 35 years, including i 8 and 35 years old) were treated with 7 treatment cycles, each consisting of 28 days ( 1 day in total, 1 tablet per day. Efficacy variable 139091.doc 200942242 Number of major efficacy variable bleeding events (including punctate hemorrhage) • Secondary efficacy variables during the 2-7th cycle • Number of days of bleeding within the 2-7th cycle (including punctate hemorrhage) • Number of withdrawal bleeding events in cycles 1 - 6 - Bleeding pattern - Days of bleeding / spotting bleeding Days of bleeding (not including spotted bleeding) - Days of spotted bleeding only

Maximum time

Length of time and length of time

- only the number of spotted bleeding events, the average length of time and the length of time range. X-cycle control of withdrawal bleeding ~ number of volunteers with or without withdrawal bleeding - length of withdrawal bleeding event - maximum intensity of withdrawal bleeding event - bleeding during the start of the withdrawal event (including points) Bleeding) Number of volunteers with or without intrapulmonary bleeding The number of bleeding events during the period and the maximum duration of bleeding within the maximum length of the cycle. Maximum intensity of bleeding events during the period 139091.doc -12- 200942242 Cycle bleeding (excluding spotted hemorrhage) - Yes Number of volunteers with no intrapulmonary bleeding - number of bleeding events during the cycle and maximum length of time - days in a cycle Number of women with intrapulmonary hemorrhage (including punctiform hemorrhage) - at least one intrapulmonary bleeding event in cycles 2-6 Number of volunteers

- Number of volunteers with at least one cycle of bleeding events in cycles 2-7 with intra-cycle bleeding (excluding spotted hemorrhage) - Number of volunteers with at least one cycle of bleeding events during Cycles 2-6 - Number of volunteers with at least one cycle of bleeding events in cycles 2-7 • Subjective assessment of treatment safety variables: • Basic test results and adverse events (AE) • Safety laboratory tests (including pregnancy tests) • Vital signs • Physical and gynaecological examinations (including breast palpation, transvaginal sonography [TVU] and cytology Pap smear). This treatment provides an acceptable bleeding profile and good tolerance. The ovulation was determined by the present invention in a randomized, double-blind clinical study. The treatment group included about 50 volunteers. The treatment was completed. The study included 1 139091.doc -13. 200942242 pre-treatment cycle and 3 treatment cycles. The primary clinical endpoint was to determine the number of volunteers with incomplete inhibition of typography. Incomplete inhibition of ovulation is defined as a Hoogland score of 6 (ovulation) during the 2nd or 3rd treatment cycle. If pps (completed juice treatment set) showed less than 5% of incomplete inhibition of ovulation, it proved successful inhibition of ovulation. This treatment effectively inhibits ovulation.

The pharmaceutical combinations of the present invention can be used in accordance with recognized pharmaceutical specifications for any particular type of unit dosage form using conventional pharmaceutically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavoring agents and/or Or adjuvants, etc., and the formulation of the main port is known to the art. For example, it usually contains a pharmaceutically acceptable carrier, such as a binder, such as silicone, gum arabic, jade starch or gelatin; excipients such as tartaric acid or cellulose; disintegrants, Such as corn house powder or alginic acid; lubricants such as stearic acid recorded in the capsule. #(四)Unit shape ... which may contain, in addition to the above types of substances

:External:: Fatty oil. A variety of other substances are present in the form of coatings or in the form of shellac. For example, a tablet or capsule as a carrier: a sugar or ugly agent may contain the active compound sweetener, a glycerin as a solubilizing agent, and a p-hydroxybenzoate as a preservative. Propyl benzoate, a material of Hu and a flavoring agent for a hydroxy suspension, peach or orange flavor. When administered at "4, these compositions may contain methylcellulose which is used to impart crystalline cellulose, alginic acid or seaweed as a suspending agent, = 139091.doc 14 200942242 degree enhancer and Sweeteners/flavoring agents are known in the art. As immediate release tablets, such compositions may contain microcrystalline cellulose 'phosphoric acid' @, starch, magnesium stearate and lactose and/or eight other excipients, binders, and scum known in the art. Degreasers, thinners and lubricants. Preferably, the snails and estradiol are formulated according to the teachings and examples of EP 1 257 280. The snail in the composition described in # is in a micronized form or another form that allows the release of drospirenone immediately after oral dosage form uptake and disintegration. Further, it is preferred to micronize estradiol. The drospirenone can be obtained from commercially available sources (for example, from Bayer pharma) or can be synthesized by conventional methods, for example, according to 6,121,465 and (9) in palpitations ~2000, 25 (12), 1247_1256. Reveal the method of synthesis. Although in accordance with the present invention, (d) preferably, the dosage unit is adapted for oral administration and gives a prescribed daily dose for oral administration, by other means known to be effective for hormonal contraception (for example via transdermal or It is also within the scope of the invention to administer a daily dose via the mucosal route. If the dosage unit is administered by an oral route, it may be necessary to adjust the daily dose. For example, t, in the case of percutaneous administration, 〇〇5 is called transdermally administered E2 is roughly equivalent to i mg administered orally, that is, compared with oral administration, 'transdermally administered E2 The availability is about 2 times higher. The bioavailability of DRSP after oral and transdermal administration is approximately the same, that is, the dose to be administered by transdermal administration is approximately the same as that given in the present specification for oral administration. Preferred pharmaceutical combination products are provided in a daily dosage unit containing the following composition 139091.doc 200942242: Stage days mg £2 mg DRSP I 8 1 3 II 8 1.5 3.0 III 8 2 3.0 Consolation fee I or none Pills - - - The dosage unit will be administered by a female patient as follows: starting with the first dose of the first phase, up to the last dose of the third phase on the 24th day of the dosing cycle, followed by 4 inactive ingredients, placebo Pills or other indications that the administration of the pill is not administered 4 days after the administration of each of the 24 dosage units. Preferably, the dosage unit is arranged in a blister pack (such as shown in the figure below) to help the female patient follow the medication regimen.

Cl = \ mg E2+3 mg DRSP ; C2 = 1.5 mg E2 + 3.0 mg DRSP ; C3 = 2 mg E2 + 3 mg DRSP ; P = placebo or no pill 139091.doc -16-

Claims (1)

200942242 VII. Patent application scope: 1. A three-stage pharmaceutical combination product comprising 24 consecutive hydrazine dosage units in three stages, comprising 6 to 10 daily dosage units in each stage of the three-stage product , wherein the amount of drospirenone in each daily dose in each stage is the same and is 1.5 mg to 3.0 mg, and the amount of 17β-estradiol is from the first 1. 〇mg 17β-estradiol in each dosage unit in one stage is increased to the amount of 2.0 mg 17β-estradiol in each dosage unit in the third stage, and wherein each day unit of the second stage The amount of 17β-estradiol is greater than 1.0 mg and less than 2.0 mg; and 4% of the placebo pill with no active ingredient, or indicating that the pill or cast is not administered 4 days after the daily administration of the 24 dosage units Other instructions with placebo pills. 2. The product of claim 3, wherein the dosage unit in each stage comprises 3·〇 mg of drospirenone. 3. The three-stage pharmaceutical combination product of claim 3, wherein the dosage unit in the second stage comprises 1.5 mg of 17β-estradiol. A two-stage pharmaceutical combination product of the first aspect of the invention, wherein the three stages each have eight hydrazine dosage units. 5. A pharmaceutical combination product according to the formula, wherein each dosage unit contains g to 1 mg of 5-decyl-(6S)-tetrahydrofolate. 6. The pharmaceutical combination product of claim 5, wherein the 5-mercapto-(6S)-tetraar arsenate is Metafolin. 7. 2 The pharmaceutical combination product of claim 6 'The individual dose units of the wipes contain 〇.4 mgil〇mg Metaf〇lin. 8. A medical kit combination product. It contains the medical device according to any one of the aforementioned claims 丨 丨 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (no) 139091.doc